A new study carried out by researchers at Technische Universität München (Munich, Germany) has discovered a previously unidentified mechanism for the regulation of programmed cell death. The results, published recently in Nature Medicine, also linked mutations in this signaling pathway with mantle cell lymphoma.
Mantle cell lymphoma is associated with poor survival rates despite the development of new treatments. This team of investigators, led by Florian Bassermann (Technische Universität München), chose this disease to investigate the mechanism of programmed cell death as it has ceased functioning in many lymphoma cells. “We urgently need to find out what’s going wrong in these cells in order to find new treatment therapies,” explained Bassermann.
Bassermann and his team started by searching for DNA errors in samples of human mantle cell lymphoma. Through these analyses they successfully identified a DNA region that was mutated in almost 30% of lymphoma patients within the study.
The identified DNA region plays a key part in producing the ubiquitin ligase FBX025. “We already knew that ubiquitin ligases are involved in breaking down proteins in cells. Now, however, we can show just how it contributes to the development of lymphoma,” commented Bassermann.
The team also discovered that FBXO25 is responsible for marking a particular protein that has to be removed before the initiation of programmed cell death. This signaling pathway for triggering programmed cell death has not previously been identified.
“If there is a defect in the ubiquitin ligase, this mechanism no longer functions. The tumor cells in question do not destroy themselves and start growing unchecked,” explained Bassermann.
In addition to this, it was determined that cells with mutated FBXO25 had a reduced response to chemotherapies, enabling the tumors to remain in a much more stable condition. Other mutations were also found in the cancerous cells, including a defect in the protein responsible for the prevention of programmed cell death, rendering it resistant to destruction.
The identification of this new signaling pathway led the scientists to begin work on a new therapeutic approach. By enabling cancerous cells to produce a functioning variant of the ubiquitin ligase, programmed cell death was reactivated in place of uncontrollable cell multiplication.
“We need to zero in on the exact defect in a tumor cell in order to adapt therapies more closely to individual types of tumors – this is particularly relevant to the field of personalized medicine. Our findings show that this signal path for mantle cell lymphoma could offer a promising approach for new therapies,” concluded Bassermann.